Thalamic Control of Propofol Phase-amplitude Coupling

Austin Soplata, Boston University

Follow this presentation at: asoplata.com/talk

Background / Methods

Phase-amplitude coupling

Native Oscillations

Native Oscillations

Propofol effects

  • Decreases H-current conductance (↓g‾H\downarrow \bar g_H):
    • The H-current is a very slow, depolarizing current that is hyperpolarization-activated (weird, right?)
  • Decreases Background Excitation (↓Iapplied\downarrow I_{applied}):
    • This hyperpolarizes the system to mimic a loss of brainstem input
  • Increases GABAAGABA_A inhibition:
    • Increases max synaptic conductance (↑g‾GABAA\uparrow \bar g_{GABA_A})
    • Increases decay time constant (↑τGABAA\uparrow \tau_{GABA_A})

Original hypothesis

Cartoon of mechanism compared to data
Cartoon of mechanism compared to data

Our model network

Sustained Alpha

Sustained alpha NOT natural

Detail: TwindowT_{window} is critical

GABAAGABA_A induces sustained alpha

Detail: Propofol alpha mechanism

Sustained alpha summary

  • GABAAGABA_A potentiation is the critical factor for sustained alpha!
  • Sustained alpha does NOT occur normally
  • GABAAGABA_A potentiation uses spindling machinery (like TwindowT_{window}) to create sustained alpha
  • Note that we have ONLY simulated an isolated thalamus so far

Alpha-SWO Coupling

Recall: SWO

Recall: Our model network

Trough-max

Peak-max

Transition example

Alpha-SWO Coupling summary

  • Overall thalamic hyperpolarization is the critical factor for switching between trough-max and peak-max!
  • GABAAGABA_A potentiation is required for any coupling, but cannot transform between PAC regimes!
  • Given SWO UP/DOWN transitions coming from cortex to thalamus,
    • trough-max alpha CAN be generated during DOWNs by the thalamus independently!
    • peak-max alpha CAN be generated during DOWNs by the thalamus independently as well, or in combination with corticothalamic spikes

Overall Modeling Conclusions

  • GABAAGABA_A potentiation is the critical factor for sustained alpha, implying a thalamic component of propofol PAC
  • Once there is sustained alpha, thalamic hyperpolarization is the critical factor for switching between trough-max and peak-max, implying a brainstem component of propofol PAC
  • You need both to get switching between peak-max and trough-max in thalamocortical output

Overall Modeling Conclusions

  • Thus, our initial model was ONLY insufficient in that there are other constraints; you also need:
    • GABAAGABA_A increase
    • g‾H\bar g_H decrease
Cartoon of mechanism compared to data
Cartoon of mechanism compared to data

Simulation Code

Our lab uses and develops the DynaSim Simulator originally created by Jason Sherfey. All the code necessary to run these simulations is available on GitHub here!